DESCRIPTION: GABA and glutamate are the two most abundant inhibitory and excitatory neurotransmitters in the brain. The concept of glutamatergic and GABAergic neurotransmission has changed considerably over the last five years, mainly because of the explosion of molecular data on the structure of glutamatergic and GABAergic receptors. It is now well established that those receptors are highly complex proteins composed of a multitude of subunits, and that the relative abundance of these subunits in the composition of the native receptors underlie many of the functional properties of the receptor channels. Another important series of findings that led to reconsider investigators view of fast excitatory synaptic transmission come from the cloning, and subsequent pharmacological and physiological studies, of a group of G-protein-linked glutamate receptors, called metabotropic receptors. These receptors modulate fast excitatory synaptic transmission and participate in the induction of long term phenomena such as synaptic plasticity and glutamate-induced neurotoxicity. The basal ganglia is a group of brain structures that play a critical role in the control of motor behaviors. A balance in the activity of GABAergic and glutamatergic networks is essential for the normal functioning of these brain structures. For instance, in Parkinson's disease, where midbrain dopaminergic neurones degenerate, the resulting imbalance between the activity of GABAergic and glutamatergic connections underlies many of the clinical manifestations of the disease. Over the last ten years, our laboratory studied in detail the pattern of distribution of GABAergic and glutamatergic terminals on different populations of neurones in the basal ganglia of monkeys. The investigators now, propose to use high resolution electron microscopic techniques to study the subsynaptic distribution of glutamate and GABA receptors associated with those afferents, and to verify the possible alterations in the expression of these receptors in animal models of Parkinson's disease. The results of those studies will provide a basic framework for understanding the complex synaptic interactions that underlie the normal functioning of the basal ganglia circuitry, and will help to identify better targets for the development of drugs that modulate abnormal glutamatergic and GABAergic neurotransmission in Parkinson's disease.